Search

Neonatal behaviors described by Als were observed in the fetus, and the relationship of these fetal motor behaviors to neonatal behavioral organization was investigated. A convenience sample of three low-risk women and their fetuses was identified early in pregnancy and followed through birth. Ultrasound imagings of these fetuses were videotaped at 12, 14, and 16 weeks of gestation, and the Assessment of Preterm Infant Behaviors (APIB) was administered at 42 weeks corrected age. Of the 20 neonatal behaviors described by Als and selected for coding in the fetus, 80% were observed at 12 weeks, 70% at 14 weeks, and 40% at 16 weeks of gestation. At 16 weeks, 87-99 percent of the behaviors scored were those considered regulatory by Als and therefore suggestive of some fetal behavioral organization at this gestational age for these subjects. No apparent relationship existed between early fetal movement in terms of the frequency and duration of the behaviors described by Als and neonatal behavioral organization as measured by the APIB. Results suggest that the neonatal behaviors described by Als can be used to describe fetal movement, but their frequency and duration may not be a sufficient measure of fetal organization. [ABSTRACT FROM AUTHOR]

Through the use of ultrasound imaging, human fetal movement can be directly observed and assessed. This capability coupled with the expansion of neuroscientific knowledge and related theories has encouraged physical therapists, obstetricians, neurologists and radiologists to work together to explore the role of fetal movement in development. Directions for fetal movement study are suggested, based on this information, and guidelines for research consistent with the dynamical systems theory are presented. [ABSTRACT FROM AUTHOR]

Trait-based frameworks are increasingly used for predicting how ecological communities respond to ongoing global change. As species range shifts result in novel encounters between predators and prey, identifying prey 'guilds', based on a suite of shared traits, can distill complex species interactions, and aid in predicting food web dynamics. To support advances in trait-based research in open-ocean systems, we present the Pelagic Species Trait Database, an extensive resource documenting functional traits of 529 pelagic fish and invertebrate species in a single, open-source repository. We synthesized literature sources and online resources, conducted morphometric analysis of species images, as well as laboratory analyses of trawl-captured specimens to collate traits describing 1) habitat use and behavior, 2) morphology, 3) nutritional quality, and 4) population status information. Species in the dataset primarily inhabit the California Current system and broader NE Pacific Ocean, but also includes pelagic species known to be consumed by top ocean predators from other ocean basins. The aim of this dataset is to enhance the use of trait-based approaches in marine ecosystems and for predator populations worldwide., (© 2024. The Author(s).)

Background: The United Kingdom (UK) was one of the first countries to pioneer heart transplantation from donation after circulatory death (DCD) donors. To facilitate equity of access to DCD hearts by all UK heart transplant centers and expand the retrieval zone nationwide, a Joint Innovation Fund (JIF) pilot was provided by NHS Blood and Transplant (NHSBT) and NHS England (NHSE). The activity and outcomes of this national DCD heart pilot program are reported., Methods: This is a national multi-center, retrospective cohort study examining early outcomes of DCD heart transplants performed across 7 heart transplant centers, adult and pediatric, throughout the UK. Hearts were retrieved using the direct procurement and perfusion (DPP) technique by 3 specialist retrieval teams trained in ex-situ normothermic machine perfusion. Outcomes were compared against DCD heart transplants before the national pilot era and against contemporaneous donation after brain death (DBD) heart transplants, and analyzed using Kaplan-Meier analysis, chi-square test, and Wilcoxon's rank-sum., Results: From September 7, 2020 to February 28, 2022, 215 potential DCD hearts were offered of which 98 (46%) were accepted and attended. There were 77 potential donors (36%) which proceeded to death within 2 hours, with 57 (27%) donor hearts successfully retrieved and perfused ex situ and 50 (23%) DCD hearts going on to be transplanted. During this same period, 179 DBD hearts were transplanted. Overall, there was no difference in the 30-day survival rate between DCD and DBD (94% vs 93%) or 90 day survival (90% vs 90%) respectively. There was a higher rate of ECMO use post-DCD heart transplants compared to DBD (40% vs 16%, p = 0.0006), and DCD hearts in the pre pilot era, (17%, p = 0.002). There was no difference in length of ICU stay (9 DCD vs 8 days DBD, p = 0.13) nor hospital stay (28 DCD vs 27 DBD days, p = 0.46)., Conclusion: During this pilot study, 3 specialist retrieval teams were able to retrieve DCD hearts nationally for all 7 UK heart transplant centers. DCD donors increased overall heart transplantation in the UK by 28% with equivalent early posttransplant survival compared with DBD donors., Competing Interests: Disclosure The authors have no conflicts of interest to declare. This research was funded by the National Health Service Blood and Transplant and National Health Service England., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

The species of the Nearctic genus Tritoxa Loew are revised. Seven species of Tritoxa are recognized, including two new species: T. californica sp. nov. (type locality: near Spring Garden, California), T. cuneata Loew, T. decipiens sp. nov. (type locality: near Smithers, British Columbia), T. flexa (Wiedemann), T. incurva Loew, T. pollinosa Cole and T. ra Harriot. One species from California and Nevada based on female specimens remains undescribed. A key to all species is provided, species are illustrated and their distributions mapped. Wing patterns may be used to differentiate among all species, although confident identification of certain sympatric species requires confirmation by examination of male genitalia.

The identification and SAR development of a series of negative allosteric modulators of the GABA A α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABA A α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Given the increasing volume of hip and knee replacement surgery with reduced hospital stays and resources, we explored technology to address gaps in patient care and enhance self-management. The team at the Holland Orthopaedic and Arthritic Centre of Sunnybrook Health Sciences Centre, which performs a high volume of joint replacement surgery, partnered with patients and a health technology company to create a mobile app: myHip&Knee. The results to date demonstrate that the app improves patient experience and reduces follow-up calls to surgeons' offices, ultimately reducing demand on healthcare resources. Early engagement of privacy and legal services, close patient and family collaboration and a well-developed evaluation strategy represent critical steps to successful development., (Copyright © 2019 Longwoods Publishing.)

NOD/Shi-scid/IL-2Rγnull (NOG) mice are humanized with CD34+ hematopoietic cells (huNOG mice) and are commonly utilized for biological or medical research on human therapeutics. In the present study, nine 26-week-old, female huNOG mice were utilized for testing proprietary immune-modulating drugs over a 3-week period at the University of Washington. Two of the 9 mice developed unilateral swelling of a tibiotarsal joint with associated paresis of the affected limb. Full necropsies were performed after euthanasia at experimental end point, and routine tissues and affected tibiotarsal joints were evaluated. An expansile, multilobular mass composed primarily of chondroid cells associated with the calcaneal tendon was present within 1 tibiotarsal joint of both mice. A small focus of well-differentiated bone was present within the mass of 1 mouse. In addition, the calcaneal periosteum was expanded by a chondroid mass in 1 mouse. The cartilaginous masses associated with the calcaneal tendon were interpreted as a hyperplastic or low-grade neoplastic process accompanied by endochondral ossification, and the mass associated with the calcaneal periosteum was interpreted as chondroid metaplasia. Although the etiology of these lesions is unclear, their prevalence in 2/9 (22%) huNOG mice is interesting and may have biological significance for future studies involving the huNOG mouse model.

Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.

Purpose: To examine the role of an advanced-practice physiotherapist (APP) with respect to (1) agreement with an orthopaedic surgeon on diagnosis and management of patients with shoulder problems; (2) wait times; and (3) satisfaction with care., Methods: This prospective study involved patients with shoulder complaints who were referred to a shoulder specialist in a tertiary care centre. Agreement was examined on seven major diagnostic categories, need for further examination and surgery, and type of surgical procedure. Wait times were compared between the APP- and surgeon-led clinics from referral date to date of initial consultation, date of final diagnostic test, and date of confirmed diagnosis and planned treatment. A modified and validated version of the Visit-Specific Satisfaction Instrument assessed satisfaction in seven domains. Kappa (κ) coefficients and bias- and prevalence-adjusted kappa (PABAK) values were calculated, and strength of agreement was categorized. Wait time and satisfaction data were examined using non-parametric statistics., Results: Agreement on major diagnostic categories varied from 0.68 (good) to 0.96 (excellent). Agreement with respect to indication for surgery was κ=0.75, p<0.001; 95% CI, 0.62-0.88 (good). Wait time for APP assessment was significantly shorter than wait time for surgeon consultation at all time points (p<0.001); the surgeon's wait time was significantly reduced over 3 years. High satisfaction was reported in all components of care received from both health care providers., Conclusions: Using experienced physiotherapists in an extended role reduces wait times without compromising patient clinical management and overall satisfaction.

Despite their high clinical and socioeconomic impacts, there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections. Here we report on a novel inhibitor of enterovirus replication, compound 1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-a]pyrazin-3-yl)phenol. This compound exhibited a broad spectrum of antiviral activity, as it inhibited all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM. After a lengthy resistance selection process, coxsackievirus mutants resistant to compound 1 were isolated that carried substitutions in their 3A protein. Remarkably, the same substitutions were recently shown to provide resistance to inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a lipid kinase that is essential for enterovirus replication, suggesting that compound 1 may also target this host factor. Accordingly, compound 1 directly inhibited PI4KIIIβ in an in vitro kinase activity assay. Furthermore, the compound strongly reduced the PI 4-phosphate levels of the Golgi complex in cells. Rescue of coxsackievirus replication in the presence of compound 1 by a mutant PI4KIIIβ carrying a substitution in its ATP-binding pocket revealed that the compound directly binds the kinase at this site. Finally, we determined that an analogue of compound 1, 3-(3-fluoro-4-methoxyphenyl)-2-methyl-N-(pyridin-4-ylmethyl)imidazo[1,2-a]pyrazin-8-amine, is well tolerated in mice and has a dose-dependent protective activity in a coxsackievirus serotype B4-induced pancreatitis model.

Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.

Background: An increase in the dialysis programme expenditure is expected in most countries given the continued rise in the number of people with end-stage renal disease (ESRD) globally. Since chronic peritoneal dialysis (PD) therapy is relatively less expensive compared with haemodialysis (HD) and because there is no survival difference between PD and HD, identifying factors associated with PD use is important., Methods: Incidence counts for the years 2003-05 were available from 36 countries worldwide. We studied associations of population characteristics, macroeconomic factors and renal service indicators with the percentage of patients on PD at Day 91 after starting dialysis. With linear regression models, we obtained relative risks (RRs) with 95% confidence intervals (CIs)., Results: The median percentage of incident patients on PD was 12% (interquartile range: 7-26%). Determinants independently associated with lower percentages of patients on PD were as follows: patients with diabetic kidney disease (per 5% increase) (RR 0.93; 95% CI 0.89-0.97), health expenditure as % gross domestic product (per 1% increase) (RR 0.93; 95% CI 0.87-0.98), private-for-profit share of HD facilities (per 1% increase) (RR 0.996; 95% CI 0.99-1.00; P = 0.04), costs of PD consumables relative to staffing (per 0.1 increase) (RR 0.97; 95% CI 0.95-0.99)., Conclusions: The factors associated with a lower percentage of patients on PD include higher diabetes prevalence, higher healthcare expenditures, larger share of private-for-profit centres and higher costs of PD consumables relative to staffing. Whether dialysis modality mix can be influenced by changing healthcare organization and funding requires additional studies.

Background and Objectives: Mortality on dialysis varies greatly worldwide, with patient-level factors explaining only a small part of this variation. The aim of this study was to examine the association of national-level macroeconomic indicators with the mortality of incident dialysis populations and explore potential explanations through renal service indicators, incidence of dialysis, and characteristics of the dialysis population., Design, Setting, Participants, & Measurements: Aggregated unadjusted survival probabilities were obtained from 22 renal registries worldwide for patients starting dialysis in 2003-2005. General population age and health, macroeconomic indices, and renal service organization data were collected from secondary sources and questionnaires. Linear modeling with log-log transformation of the outcome variable was applied to establish factors associated with survival on dialysis., Results: Two-year survival on dialysis ranged from 62.3% in Iceland to 89.8% in Romania. A higher gross domestic product per capita (hazard ratio=1.02 per 1000 US dollar increase), a higher percentage of gross domestic product spent on healthcare (1.10 per percent increase), and a higher intrinsic mortality of the dialysis population (i.e., general population-derived mortality risk of the dialysis population in that country standardized for age and sex; hazard ratio=1.04 per death per 10,000 person years) were associated with a higher mortality of the dialysis population. The incidence of dialysis and renal service indicators were not associated with mortality on dialysis., Conclusions: Macroeconomic factors and the intrinsic mortality of the dialysis population are associated with international differences in the mortality on dialysis. Renal service organizational factors and incidence of dialysis seem less important.

Background: Applying the Kidney Disease Outcomes Quality Initiative definitions of chronic kidney disease (CKD), it appears that CKD is common. The increased recognition of CKD has brought with it the clinical challenge of translating into practice the implications for the patient and for service planning. To understand the clinical relevance and translate that into information to support individual patient care and service planning, we explored clinical outcomes in a large British CKD cohort, identified through routine opportunistic testing, with a 6-year follow-up (≈ 13,000 patient-years)., Methods: A cohort had previously been identified with CKD-sustained reduced eGFR over at least 3 months and case note review. Six-year (13,339 patient-years) follow-up for renal replacement therapy (RRT) initiation and death was achieved through data linkage. Age- and sex-specific mortality rates were compared to the general population., Results: Of 3414 individuals (most Stage 3b-5), median age 78.6 years, followed for 13 339 patient-years, 170 (5%) initiated RRT and 2024 (59%) died without initiating RRT. RRT initiation rates decreased with age from 14.33 to 0.65 per 100 patient-years among those aged 15-25 and 75-85 years at baseline but the actual numbers initiating RRT increased from 6 to 34, respectively. RRT initiation rates were lower for female sex, absence of macroalbuminuria and less advanced CKD stage. Mortality rates increased with age from 2 to 34 per 100 patient-years for those aged 15-45 and > 85 years at baseline, an excess of 2 and 17 per 100 patient-years over that of the general population, respectively. However, the increase in relative risk was 19-fold for those aged 15-45 years and just 2-fold in those > 85 years. These data have been converted into simple tools for considering individual patients' risk and informing service planning., Conclusions: The contrast between relative and absolute risk for both RRT initiation and mortality by age group illustrates the difficulties for planning services. The challenge that now faces clinicians is how to appropriately identify which elderly patients with CKD are at high risk of poor outcome.

Background: Incidence rates of renal replacement therapy (RRT) for end-stage renal disease vary considerably worldwide. This study examines the independent association between the general population, health care system and renal service characteristics and RRT incidence rates., Methods: RRT incidence data (2003-2005) were obtained from renal registries; general population age and health and macroeconomic indices were collected from secondary sources. Renal service organization and resource data were obtained through interviews and questionnaires. Linear regression models were built to establish the factors independently associated with RRT incidence, stratified by the Human Development Index where required. False discovery rate (FDR) correction was adjusted for multiple testing., Results: Across the 46 countries (population 1.25 billion), RRT incidence rates ranged from 12 to 455 (median 130) per million population. Gross domestic product (GDP) per capita [incidence rate ratio (IRR): 1.02 per $1000 increase, P(FDR) = 0.047], percentage of GDP spent on health care (IRR: 1.11 per % increase, P(FDR) = 0.006) and dialysis facility reimbursement rate relative to GDP (IRR: 0.76 per GDP per capita-sized increase in reimbursement rate, P(FDR) = 0.007) were independently associated with RRT incidence. In more developed countries, the private for-profit share of haemodialysis facilities was also associated with higher incidence (IRR: 1.009 per % increase, P(FDR) = 0.003)., Conclusions: Macroeconomic and renal service factors are more often associated with RRT incidence rates than measured demographic or general population health status factors.

Amalgamation of the structure-activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus monkey as determined by displacement of a PET tracer ligand.

Scaffold hopping from a non-basic series of 5-HT(2A) receptor antagonists developed in-house that possessed reduced activity in vivo enabled the discovery of a novel series of diaryl sulfones that gave excellent occupancy on oral dosing. Not only does this work further demonstrate that oral bioavailability of a given series can be enhanced by improving physicochemical parameters such as log P, but it corroborates the growing evidence that a protonated amine is not essential for affinity at aminergic GPCRs., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Rates of initiation of renal replacement therapy (RRT), use of home modalities of treatment and patient outcomes vary considerably between countries. This paper reports the methods and baseline characteristics of countries participating in the EVEREST study (n = 46), a global collaboration examining the association between medical and non-medical factors and RRT incidence, modality mix and survival. Numbers of incident and prevalent patients were collected for current (2003-05) and historic (1983-85, 1988-90, 1993-95 and 1998-2000) periods stratified, where available, by age, gender, treatment modality and cause of end stage renal disease (diabetic versus non-diabetic). General population age and health indicators and national-level macroeconomic data were collected from secondary data sources. National experts provided primary data on renal service funding, resources and organization. The median (inter quartile range) RRT incidence per million of the population (pmp) was 130 pmp (102-167 pmp). The general population life expectancy at 60 was 22.1 years (19.7-23.1 years) and 6.9% had diabetes mellitus (5.4-9.0%). Healthcare spending as a percentage of gross domestic product was 8.1% (5.6-9.3%). Countries averaged nine dialysis facilities pmp (4-12 pmp), with 69.0% (43.9-99.0%) owned by the public or private not-for-profit sector. The number of nephrologists ranged from 0.5 to 48 pmp (median 12 pmp). The heterogeneity of EVEREST countries will enable modelling to examine the independent association between medical and non-medical factors on RRT epidemiology.

Background: Almost 30% of chronic haemodialysis (HD) patients are dependent on central venous catheters (CVCs) for their vascular access, and catheter-related bacteraemia (CRB) is the major reason for catheter loss and has been associated with substantial morbidity, including meta-static infections. This systematic review evaluates the benefits and harms of antimicrobial interventions for the prevention of catheter-related infections (CRIs)., Methods: MEDLINE (1950-May 2009), EMBASE (1980-May 2009) CENTRAL (up to May 2009) and bibliographies of retrieved articles were searched for relevant RCTs. Analysis was by a random effects model and results expressed as rate ratio, relative risk (RR) and weighted mean difference (WMD) with 95% confidence intervals (CI)., Results: A total of 29 trials with 2886 patients and 3005 catheters were included. Antimicrobial catheter locks (AMLs) significantly reduced the rates of CRBs (rate ratio, 0.33, 95% CI 0.24-0.45) and exit-site infections (ESIs) (rate ratio 0.67, 95% CI 0.47-0.96). Exit-site antimicrobial application also significantly reduced the rates of CRBs (rate ratio 0.21, 95% CI 0.12-0.36) and ESIs (rate ratio 0.22, 95% CI 0.10-0.47). Antimicrobial coating of HD catheters and the use of peri-operative antimicrobials did not result in significant reduction in rates of CRBs and ESIs., Conclusion: The use of AMLs and exit-site antimicrobials are useful measures in the reduction of CRIs, whereas antimicrobial impregnated catheters and peri-operative systemic antimicrobial administration have not been found to be beneficial. Further head-to-head trials of various AMLs and exit-site antimicrobials are needed to know about their comparative clinical efficacy.

3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine (MRK-016) is a pyrazolotriazine with an affinity of between 0.8 and 1.5 nM for the benzodiazepine binding site of native rat brain and recombinant human alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. It has inverse agonist efficacy selective for the alpha5 subtype, and this alpha5 inverse agonism is greater than that of the prototypic alpha5-selective compound 3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-hdyl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine (alpha5IA). Consistent with its greater alpha5 inverse agonism, MRK-016 increased long-term potentiation in mouse hippocampal slices to a greater extent than alpha5IA. MRK-016 gave good receptor occupancy after oral dosing in rats, with the dose required to produce 50% occupancy being 0.39 mg/kg and a corresponding rat plasma EC(50) value of 15 ng/ml that was similar to the rhesus monkey plasma EC(50) value of 21 ng/ml obtained using [(11)C]flumazenil positron emission tomography. In normal rats, MRK-016 enhanced cognitive performance in the delayed matching-to-position version of the Morris water maze but was not anxiogenic, and in mice it was not proconvulsant and did not produce kindling. MRK-016 had a short half-life in rat, dog, and rhesus monkey (0.3-0.5 h) but had a much lower rate of turnover in human compared with rat, dog, or rhesus monkey hepatocytes. Accordingly, in human, MRK-016 had a longer half-life than in preclinical species ( approximately 3.5 h). Although it was well tolerated in young males, with a maximal tolerated single dose of 5 mg corresponding to an estimated occupancy in the region of 75%, MRK-016 was poorly tolerated in elderly subjects, even at a dose of 0.5 mg, which, along with its variable human pharmacokinetics, precluded its further development.

The Joint Health and Disease Management Program in the Toronto Central Local Health Integration Network (TC LHIN) is envisioned as a comprehensive model of care for patients with hip and knee arthritis. It includes access to assessment services, education, self-management programs and other treatment programs, including specialist care as needed. As the first phase of this program, the hospitals in TC LHIN implemented a Hip and Knee Replacement Program to focus on improving access and quality of care, coordinating services and measuring wait times for patients waiting for hip or knee replacement surgery. The program involves healthcare providers, consumers and constituent hospitals within TC LHIN. The approach used for this program involved a definition of governance structure, broad stakeholder engagement to design program elements and plans for implementation and communication to ensure sustainability. The program and approach were designed to provide a model that is transferrable in its elements or its entirety to other patient populations and programs. Success has been achieved in creating a single wait list, developing technology to support referral management and wait time reporting, contributing to significant reductions in waits for timely assessment and treatment, building human resource capacity and improving patient and referring physician satisfaction with coordination of care.

A new model of care has been implemented at the Sunnybrook Holland Orthopaedic and Arthritic Centre that expands the role of physiotherapists to improve access and quality of care for patients requiring hip and knee replacement surgery. An advanced practice physiotherapist (APP) role was created to support both referral management and post-operative care to reduce surgeon workload and better streamline services. This article describes our nine-step framework for implementing an APP role and can be used as a template for other organizations evolving similar roles. The framework was adapted from the participatory, evidence-based, patient-focused process for the development of an advanced practice nurse role. Key steps include (1) obtaining stakeholder consensus, (2) identifying barriers and facilitators and (3) developing the necessary administrative and training supports as well as clinical protocols and an evaluation framework. Approaching change in a series of small steps (plan-do-study-act [PDSA] methodology) alongside existing processes has facilitated buy-in and role acceptance. The early and continued involvement of decision-makers within the organization has been paramount to successful implementation. In addition, patient input has been central to the evolution of the role, with patient satisfaction a key indicator. The new role and model of care reconfigures traditional roles and introduces a team approach that results in timely access to care for patients. Benefits include an improved assessment process, enhanced education across the care continuum and improved coordination and delivery of services.

The longitudinal profiles of ultrashort relativistic electron bunches at the soft x-ray free-electron laser FLASH have been investigated using two single-shot detection schemes: an electro-optic (EO) detector measuring the Coulomb field of the bunch and a radio-frequency structure transforming the charge distribution into a transverse streak. A comparison permits an absolute calibration of the EO technique. EO signals as short as 60 fs (rms) have been observed, which is a new record in the EO detection of single electron bunches and close to the limit given by the EO material properties.

Background: A systematic review of randomized controlled trials (RCTs) comparing continuous ambulatory peritoneal dialysis (CAPD) with all forms of automated peritoneal dialysis (APD) was performed to assess their comparative clinical effectiveness., Methods: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, were searched for relevant RCTs. Analysis was by a random effects model and results expressed as relative risk (RR) and weighted mean difference (WMD) with 95% confidence intervals (CI)., Results: Three trials (139 patients) were identified. APD when compared to CAPD was found to have significantly lower peritonitis rates (two trials, 107 patients, rate ratio 0.54, 95% CI 0.35-0.83) and hospitalization rates (one trial, 82 patients, rate ratio 0.60, 95% CI 0.39-0.93) but not exit-site infection rates (two trials, 107 patients, rate ratio 1.00, 95% CI 0.56-1.76). However no differences were detected between APD and CAPD in respect to risk of mortality (RR 1.49, 95% CI 0.51-4.37), peritonitis (RR 0.75, 95% CI 0.50-1.11), switching from the original peritoneal dialysis (PD) modality to a different dialysis modality including an alternative form of PD (RR 0.50, 95% CI 0.25-1.02), PD catheter removal (RR 0.64, 95% CI 0.27-1.48) and hospital admissions (RR 0.96, 95% CI 0.43-2.17). Patients on APD were found to have significantly more time for work, family and social activities., Conclusions: APD appears to be more beneficial than CAPD, in terms of reducing peritonitis rates and with respect to certain social issues that impact on patients' quality of life. Further, adequately powered trials are required to confirm the benefits for APD found in this review and detect differences with respect to other clinically important outcomes that may have been missed by the trials included in this review due to their small size and short follow-up periods.

Background: Acute renal failure (ARF) is a diverse condition with no standardized definition and is managed in several sub-specialty areas within hospitals. Its incidence and aetiology are unknown and studies show a wide range of incidences. ARF is becoming more common as the population ages leading to the hypothesis that the incidence is much higher than previous estimates., Methods: This prospective population study investigated the incidence, aetiology and outcomes of ARF based on a standardized classification of ARF treated by renal replacement therapy (RRT) in all sub-specialty areas within hospitals where such treatment takes place. Data were collected prospectively on all patients starting RRT for ARF within three 12-week periods in 2002., Results: Two hundred eighty-six adults per million population (pmp) per year received RRT for ARF. The incidence increased with age and pre-existing comorbid illness. Two hundred twelve adults pmp per year had no evidence of pre-existing chronic kidney disease (CKD) and the remainder had acute on CKD. The median age was 67 years. Fifty-one percent of the patients received their first RRT treatment in a critical care setting. Sepsis was the most common aetiological insult contributing to ARF in 48% of the patients. Mortality was high with 48% dying within 90 days of starting RRT. Age, comorbidity, sepsis and recent surgery were independent risk factors for death in those with no pre-existing CKD., Discussion: This is the first national study to describe ARF treated with RRT in all hospital locations. The hypothesis that ARF occurs more frequently than previously thought has been confirmed. This study provides data upon which to base effective decision making for prevention, patient care and resource planning for patients with ARF.

Background: Renal replacement therapy (RRT) for acute renal failure (ARF) can be applied intermittently (IRRT) or continuously (CRRT). It has been suggested that CRRT has several advantages over IRRT including better haemodynamic stability, lower mortality and higher renal recovery rates., Objectives: To compare CRRT with IRRT to establish if any of these techniques is superior to each other in patients with ARF., Search Strategy: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL). Authors of included studies were contacted, reference lists of identified studies and relevant narrative reviews were screened. Search date: October 2006., Selection Criteria: RCTs comparing CRRT with IRRT in adult patients with ARF and reporting prespecified outcomes of interest were included. Studies assessing CAPD were excluded., Data Collection and Analysis: Two authors assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes or mean difference (WMD) for continuous data with 95% confidence intervals (CI)., Main Results: We identified 15 studies (1550 patients). CRRT did not differ from IRRT with respect to in-hospital mortality (RR 1.01, 95% CI 0.92 to 1.12), ICU mortality (RR 1.06, 95% CI 0.90 to 1.26), number of surviving patients not requiring RRT (RR 0.99, 95% CI 0.92 to 1.07), haemodynamic instability (RR 0.48, 95% CI 0.10 to 2.28) or hypotension (RR 0.92, 95% CI 0.72 to 1.16) and need for escalation of pressor therapy (RR 0.53, 95% CI 0.26 to 1.08). Patients on CRRT were likely to have significantly higher mean arterial pressure (MAP) (WMD 5.35, 95% CI 1.41 to 9.29) and higher risk of clotting dialysis filters (RR, 95% CI 8.50 CI 1.14 to 63.33)., Authors' Conclusions: In patients who are haemodynamically stable, the RRT modality does not appear to influence important patient outcomes, and therefore the preference for CRRT over IRRT in such patients does not appear justified in the light of available evidence. CRRT was shown to achieve better haemodynamic parameters such as MAP. Future research should focus on factors such as the dose of dialysis and evaluation of newer promising hybrid technologies such as SLED. Triallists should follow the recommendations regarding clinical endpoints assessment in RCTs in ARF made by the Working Group of the Acute Dialysis Quality Initiative Working Group.

This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.

Background: Peritoneal dialysis (PD) can be performed either manually as in continuous ambulatory peritoneal dialysis (CAPD) or using mechanical devices as in automated PD (APD). APD has been considered to have several advantages over CAPD such as reduced incidence of peritonitis, mechanical complications and greater psychosocial acceptability., Objectives: To assess the comparative efficacy of CAPD and APD in patients who are dialysed for end-stage renal disease (ESRD)., Search Strategy: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Renal Group's specialised register and CINAHL. Authors of included studies were contacted, reference lists of identified RCTs and relevant narrative reviews were screened. Date of most recent search: May 2006, Selection Criteria: RCTs comparing CAPD with APD in patients with ESRD., Data Collection and Analysis: Data were abstracted independently by two authors onto a standard form. Relative risk (RR) for dichotomous data and a mean difference (MD) for continuous data were calculated with 95% confidence intervals (CI)., Main Results: Three trials (139 patients) were included. APD did not differ from CAPD with respect to mortality (RR 1.49, 95% CI 0.51 to 4.37), risk of peritonitis (RR 0.75, 95% CI 0.50 to 1.11), switching from original PD modality to a different dialysis modality (RR 0.50, 95% CI 0.25 to 1.02), hernias (RR 1.26, 95% interval 0.32 to 5.01), PD fluid leaks (RR 1.06, 95% CI 0.11 to 9.83), PD catheter removal (RR 0.64, 95% CI 0.27 to 1.48) or hospital admissions (RR 0.96, 95% CI 0.43 to 2.17). There was no difference between either PD modality with respect to residual renal function (MD -0.17, 95% CI -1.66 to 1.32). One study found that peritonitis rates and hospitalisation were significantly less in patients on APD when results were expressed as episodes/patient-year. Another study found that patients on APD had significantly more time for work, family and social activities., Authors' Conclusions: APD has not been shown to have significant advantages over CAPD in terms of important clinical outcomes. APD may however be considered advantageous in select group of patients such as in the younger PD population and those in employment or education due to its psychosocial advantages. There is a need for a RCT comparing CAPD with APD with sufficiently large patient numbers looking at important clinical outcomes including residual renal function, accompanied by an economic evaluation to clarify the relative clinical and cost-effectiveness of both modalities.

Background: Renal replacement therapy (RRT) for end-stage kidney disease (ESKD) can be achieved by several interventions including haemodialysis (HD), peritoneal dialysis (PD) and kidney transplantation. HD, haemofiltration (HF), haemodiafiltration (HDF) and acetate-free biofiltration (AFB) are extracorporeal RRT methods. It has been suggested that HF and HDF may reduce the frequency and severity of intradialytic and post-dialytic adverse symptoms and may be more effective than HD in the removal of high molecular weight molecules., Objectives: To compare convective modes of extracorporeal RRT (HF, HDF or AFB) with HD and to establish if any of these techniques is superior to each other in patients with ESKD., Search Strategy: We searched MEDLINE (1966-2006), EMBASE (1980-2006), Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library issue 2, 2006) and CINAHL (1872-2006). Authors of included studies were contacted, reference lists of identified RCTs and relevant narrative reviews were screened., Selection Criteria: RCTs comparing HF, HDF, AFB and HD for ESKD were included. Trials enrolling any patient undergoing RRT for ESKD were included., Data Collection and Analysis: Two authors independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes or weighted mean difference (MD) for continuous data with 95% confidence intervals (CI). Heterogeneity was measured using the Chi-square (chi(2)) and I(2) statistic., Main Results: Twenty studies (657 patients) were included. Seventeen studies compared HF, HDF or AFB with HD, two compared HDF with AFB and one compared HF with HDF. The studies were generally small with suboptimal quality. Convective modalities (HF, HDF, AFB) did not differ significantly from HD for mortality (RR 1.68, 95% CI 0.23 to 12.13; chi(2)= 2.58, P = 0.11, I(2) = 61.2%), number of hospital admissions/year (MD 0.20, 95% CI -0.07 to 0.47) and dialysis adequacy (Kt/V: MD 0.09, 95% CI 0.02 to 0.17; chi(2) = 3.73, P = 0.29, I(2) = 19.6%). No study assessed number of dialysis treatments associated with "any adverse symptoms", sessions that were stopped early, change of dialysis modality or dialysis-related amyloidosis., Authors' Conclusions: We were unable to demonstrate whether convective modalities (either HF, HDF or AFB) have significant advantages over HD with regard to clinically important outcomes of mortality, dialysis-related hypotension and hospitalisation. More adequately-powered good quality RCTs assessing clinically important outcomes (mortality, hospitalisation, quality of life) are needed.

Based on an existing series of 5-HT2A receptor ligands containing a basic nitrogen, we designed a non-basic lead that had reduced affinity for both the 5-HT2A receptor and the IKr potassium channel. The present paper describes the development of this lead to a novel series of non-basic piperidine sulfonamides and amides that have high affinity for the 5-HT2A receptor, whilst maintaining excellent selectivity over off target activities such as the IKr channel. This work has shown that the proposed pharmacophore model for the 5-HT2A receptor which suggests that a basic nitrogen is required for the binding of ligands is questionable.

The electro-optic effect between an ultrafast optical probe pulse and an ultrashort terahertz pulse is shown to depend on the time derivatives of the product of the probe and terahertz electric fields. Application of this theory to temporally resolved single-shot terahertz detection techniques, where the electro-optic effect is temporally localized within an optical probe pulse, shows that the description presented here differs fundamentally and verifiably from that commonly used in literature.

(3-Tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d] [1,2,4]triazine was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5-containing receptors, which enhances performance in animal models of cognition. The routes of metabolism of this compound in rat, dog, rhesus monkey and human in vitro systems, and in vivo in rat, dog and rhesus monkey have been characterized. The current study demonstrates that both a cytosolic oxidative reaction and cytochrome P450 play important roles in the metabolism of the compound. Chemical inhibition studies showed the oxidation in human cytosol to be catalysed predominantly by aldehyde oxidase rather than the related enzyme, xanthine oxidase. The aldehyde oxidase-mediated metabolites were present in vitro and in vivo in both rat and rhesus monkey, and also in vitro in man. They were absent both in vitro and in vivo in dog.

Alpha5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has inverse agonist efficacy selective for the alpha5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABA(A) receptors containing an alpha5 subunit. In a mouse hippocampal slice model, alpha5IA significantly enhanced the burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that alpha5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, alpha5IA significantly enhanced performance in a rat hippocampal-dependent test of learning and memory, the delayed-matching-to-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice alpha5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, alpha5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABA(A) alpha5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.

(3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (1) was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5 receptors and enhances performance in animal models of cognition. The routes of metabolism of this compound in vivo in rat have been well characterised, the identities of the major metabolites are confirmed by synthesis and their biological profiles were evaluated. An unusual oxidation of the pyrazolo[1,5-d][1,2,4]triazine core to the corresponding pyrazolo[1,5-d][1,2,4]triazin-4(5H)-one scaffold by aldehyde oxidase has been observed.

The demand for hip replacements is on the rise; however, despite commonly employed post-operative positional and activity restrictions, limited evidence exists to substantiate such practices. Guidelines provide a means of assisting the healthcare team in decision-making; however, when a clinical decision has to be made in the absence of scientific evidence, guideline developers rely on consensus processes. A formal consensus process based on a nominal group technique was used to incorporate the scientific evidence and practitioner experience for the development of primary total hip replacement guidelines at a specialized orthopaedic tertiary care facility. Agreement was reached regarding a number of practice issues, which historically had varied among the surgeons. Given the lack of available guidance on how to synthesize research findings in conjunction with expert opinion, the process we employed has been described so that others may use, modify and refine it. Further scientific inquiry into safe activity resumption post-total hip replacement is warranted.